Antibacterial compositions and methods

ABSTRACT

Imines of 2-formylquinoxaline-3-carboxylic acid-1,4-dioxides and their salts are obtained through treatment of the lactone or a salt of 2-dihydroxymethylquinoxaline-N,N-dioxide-3-carboxylic acid with a reactant bearing a free primary amino group. The resultant compounds and their non-toxic salts are antibacterial agents and can be incorporated in pharmaceutical compositions and feedstuffs for this use. A typical embodiment is 2(carbomethoxyhydrazonomethyl)-quinoxaline-3-carboxylic acid-1,4dioxide.

United States Patent Seng et al. Sept. 2, 1975 ANTIBACTERIALCOMPOSITIONS AND METHODS [56] References Cited [75] Inventors: FlorinSeng, Cologne-Buchheim; UNITED STATES PATENTS Kurt Ley,Odenthal-Gloebusch; 3,371,090 2/1968 Johnston 260/240 G fgfi jgig u fFOREIGN PATENTS OR APPLICATIONS 3 1 53 e e a 0 1,215,815 12/1970 UnitedKingdom 260/250 R [73] Assi nee: Bayer Aktiengesellschaft, GermanyPrimary Examiner.lerome D. Goldber g g [22] Filed: Aug. 16., 1973ABSTRACT PP 389,033 lmines of 2-f0rmylquinoxaline-3-carboxylic acid-1,4-Related Application Data dioxides and their salts are obtained throughtreat- [62] Division of Set. No. 323,953, Jan. 15, 1973, which is of thesalt of a division of Sen 130.007 March 31, 1971, PatdlhydroxymethylqumoxalIne-N,N-d1ox1de-3-carboxyl1c No 3 819616 acid witha reactant bearing a free primary amino group. The resultant compoundsand their non-toxic [30] Foreign Application priority Data salts areantibacterial agents and can be incorporated A 2 1970 German 2015676 inpharmaceutical compositions and feedstuffs for this pr. y use A ypicalembodiment is 2- 424 250 5" A6lk 2/7/00 carboxylic acid-l,4-dioxide [58]Field of Search 424/250 38 Claims, No Drawings ANTIBACTERIALCOMPOSITIONS AND METHODS This is a division of application Ser. No.323,953, filed Jan. 15, 1973, which is a divisional of Ser. No. 130,007,filed Mar. 31, 1971, now US. Pat. 3,819,616.

The present invention relates to new imines of 2-formyl-quinoxaline-3-carboxylic acid- 1 ,4 dioxides and their salts, toprocesses for their preparation, to the use of the new compounds asmedicaments in human medicine and veterinary medicine, to their use asfeedstuff additives, especially in raising young animals or fatstock,and to compositions adapted to this use.

The new imines and salts have the general formula:

i COOY I CH==N--R wherein Y is hydrogen, an alkali metal cation or thecation R NH and each of R and R is identical to or different from theother and is selected from the group consisting of a. alkyl, substitutedalkyl or cycloalkyl; b.

in which each of R and R when taken independently is identical to ordifferent from the other, and is selected from the group consisting ofhydrogen, alkyl or substituted alkyl, or when R and R are takentogoether with the nitrogen atom to which they are attached a 5- to7-menibered heterocyclic ring optionally containing as a ring memberoxygen, sulphur, S0 or N-alkyl;

R] -NH(-N in which X is O, S or NH and, R and R are as above defined;

NH- fi o-R in which R is alkyl or substituted alkyl;

in which R is phenyl, pyridyl or norbornyl, and

X is as defined above;

in which R, R and X are as defined above; or

in which each of R and R when taken independently is identical to ordifferent from the other and is selectedfrom the group consisting ofhydrogen, alkyl or hydroxyalkyl of from l to 4 carbon atoms, or. 'when Rand R are taken together with the nitrogen atom to which they areattached, a 6-membered heterocyclic ring optionally containingas a ringmember oxygen or S0 in which X is O, S or NH, and R and R are as hereindefinedy d.

in which R is alkyl or hydroxyalkyl of from 1 to 4 carbon atoms; and

contain from 3 to 7, preferably 5 to 7, carbon atoms and include bothmonocyclic and bicyclic ring systems.

These aliphatic or cycloaliphatic groups can be optionally substituted,for example, by hydroxy, alkoxy, or acyloxy, the alkoxy and acyloxygroups containing 1 to 4, preferably 1 or 2, carbon atoms. The hydroxygroup is the preferred substituent. Typical aliphatic and cycloaliphaticgroups thus include methyl, ethyl, npropyl, isopropyl, n-butyl,isobutyl, tert.-butyl, npentyl, isopentyl, hexyl, 2-hydroxyethyl,cyclopropyl, cyclopentyl, cyclohexyl, bicyclo-(2,2,l)heptyl (norbornyl),and the like.

The substituents R and R are hydrogen or alkyl of from 1 to 4,preferably 1 or 2, carbon atoms. These alkyl groups can be optionallysubstituted with hydroxy, alkoxy or acyloxy, alkoxy and acyloxy groupscontaining 1 to 4, preferably 1 or 2, carbon atoms. Thus included areethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert.-butyl, as wellas the corresponding groups substituted by hydroxy. I

R and R when taken together with the nitrogen atom to which they areattached, can also form a heterocyclic ring, preferably containing 6ring members, and preferably with an oxygen atom, a sulphur atom, an N-alkyl group containing 1 to 4, preferably 1 or 2, carbon atoms, or theS0 group, as a ring member in the pposition relative to the nitrogenatom to which R and R are attached.

R is an alkyl of from 1 to 4, preferably 1 or 2, carbon atoms which mayalso be optitonally substituted by hydroxy, alkoxy, acyloxy, alkoxy andacyloxy containing 1 to 4, preferably 1 or 2, carbon atoms. The hydroxygroup is a particularly preferred substituent. R thus embraces suchgroups as methyl, ethyl, Z-hydroxyethyl and the like.

The alkali metal cation Y is, for example, that of sodium or potassium,preferably that of sodium.

R is phenyl, pyridyl or norborn-2-yl. When R is pyridyl, it can bebonded in the 2-, 3- or 4-position relative to the pyridyl nitrogenatom.

The above class of imines are obtained according to the process of thepresent invention by treatment of loxo-3-hydroxyl ,3-dihydro-furo-(3,4-b )-quinoxaline- 4,9-dioxide, which has the formula:

or a salt thereof ofthe formula with an amine of the general formula HNR, in which R is as previously defined, M is an alkali metal oralkaline earth metal cation and x is l or 2.

The salts of the formula can be obtained from the lactone of formulathrough treatment with alkali metal or alkaline earth metal hydrogencarbonates.

M is preferably the cation of sodium, potassium or most preferablycalcium.

Both inorganic and organic polar solvents can be used as diluents forthe reaction according to the invention, such as for example water,lower aliphatic alcohols of l to 4 carbon atoms, lower aliphaticnitriles such as acetonitrile, tetrahydrofurane, dioxane,dimethoxyethane, pyridine, dimethylformamide and the like.

The reaction according to the invention is carried out at a temperatureof about 0 C to about C, preferably 20 C to about 35 C. In practice, thelactone or lactone salts are dissolved orsuspended in the diluent, andthis solution or suspension is then treated with an appropriate quantityof the amine. The formation of the imine or of the imine salt takesplace in a weakly exothermic reaction and the final product is thenisolated through conventional methods.

The imine salts (l can also be prepared by the reaction of the freeacids with amines.

The salts may be obtained in a subsequent step by conventionaltechniques or directly in the reaction of the lactone with the amine. Ifabout 2 mols of the amine per mol of lactone are employed, the productwill be in the form of that amine salt. If an alkali metal salt oralkaline earth metal salt of the lactone is employed, or if it isdesired to obtain the free acid from the lactone, only about 1 mol ofthe amine per mol of the lactone or salt is required.

The course of the process according to the invention can thus beillustrated by the following equations:

OON a The following examples will serve to further typify the nature ofthis invention without being a limitation on the scope thereof.

EXAMPLE 1 coon n N 3 in the form of yellow crystals, which afterrecrystallisation from isopropanol melt at l23-25 C, with decomposition.

Analysis: C H N O (molecular weight 334). Calculated: C 57.5% H 6.6% N16.8%. Found: C 57.1% H 5.8% N 16.8%.

EXAMPLE 2 27.4 g (0.1 mol) of the Na salt of2-(dihydroxymethyl)-3-carboxylic acid-quinoxaline-di-N- H NTCOONa 3H2N-%CH3 cu: -CH

oxide are dissolved in ml of water and 7.3 g (0.1 mol) oftert.-butylamine are added. The temperature is kept at 25 C by cooling.After 1 hour, the solution is evaporated in vacuo and 32 g of thecompound of the formula 'N 000m 1 I i CH=N--CH are obtained in the formof yellow crystals which after recrystallisation from acetonitrile/watermelt at 228 C, with decomposition.

Analysis: C H N NaO (molecular weight 31 l Calculated: C 54.0% H 4.5% N13.5% Na 7.4%. Found: C 53.7% H 4.9% N 13.5% Na 6.9%.

The l-oXo-3-hydroxy-l ,3-dihydro-furo( 3 ,4- b)quinoxaline-4,9-dioxideof the formula (I) required as the starting compound can be obtained asfollows:

30.7 g (0.1 mol) of 2-bismethoxy-methyl-3-dimethylaminocarbonyl-quinoxaline-l ,4-di-N-oxide are introduced into100 ml of 10% strength aqueous hydrochloric acid. A clear solutionresults, and after a short time the compound according to the inventionseparates out in the form of a yellow precipitate, which is filtered offafter 6 hours. 17 g (72.6% of theory) ofl-oxo-3-hydroxy-1,3-dihydro-furo-(3,4b)quinoxaline- 4,9-dioxide are thusobtained in the form of yellow crystals.

The compound is purified by dissolving it in sodium The lactone (9) issuspended inwater and approxibicarbonate solution, filtering andacidifying the filmately the stoichiometrically required amount of thetrate. The purified compound melts at 156 159 C, alkali metal hydrogencarbonate or alkaline earth metal whilst foaming. hydrogen carbonate isadded at room temperature. The Analysis: C H N O (235). Calculated: C51.3% H 5 salt of the lactone (10), thus produced, precipitates, 2.6% N12.0%. Found: C 52.0% H 2.8% N 12-6% after evaporation of the solutionif necessary, and can The alkali metal salts or alkaline earth metalsalts of b i l d i h usual manner 1-o o-3-hyd o y-1, -di y )q a i Thefollowing are obtained analogously to Examples 4,9-dioxide can bemanufactured as follows: 1 and 2:

10 Example Melting Point (C) No. Compound (decomposition) ('ontinuedMelting Point (C) Example (decomposition Compound Nov COONu COONa O O Tl o 0 T N ICOONa COONa COONa show a very good antibacterial action, andthe range of action encompasses both Gram-negative and Grampositivebacteria. The chemotherapeutic activity of the compounds according tothe invention permits their use in human medicine and in veterinarymedicine.

' some of the new compounds shown in Table 1 (MIC) were determined bythe plate test in an agar medium of the following composition:

proteose peptone 10.0 g per litre veal extract (solids) 10.0 g dextroseg sodium chloride 31) g Continued Example Melting Point (C) No. Compound(decomposition 26 o 0 275 COONa HZN 3 CH=N-NH-C M II l NH 0 27 I87 COONaCH=NNHC- i H 0 28 (T) 209 N COONa CH=N-NH-'C- COOH ci-i=N NH-c00C1,H,.-,

COOH

CH=NNHCOOCH2CH,OH

As has already been mentioned, the new compounds 45 disodium phosphate2.0 g of the invention surprisingly show an excellent chemoz zg ifjfiztherapeutic activity. Their chemotherapeutic action guaninehydrochloride 8 was examined both in animal experiments (oral and i:8-8: s X311 subcutaneous administration) with acute bacterial inagar [20fections, and in vitro. In both cases the compounds 50 5.10 X 10 germswere inoculated per plate. Readings were taken after 24 and 48 hours,and the incubation temperature was about 37 C.

Table l MlC in -y/ml of medium Compound of Compound of Compound ofBacterium Example 10 Example 12 Example 13 Table 1Continued BacteriumMIC MIC in 7/ml of medium M f 100 Compound of Compound of Compound ofggg ga Hep cum Bacterium Example 10 Example l2 Example 13 5 H granularum25 bovirhinis 200 Klebsiella pneumonia 63 100 Kl t 'ell nifjloni a 8085In animal experiments on mice, the effective 100% Staphylococcus 0 d (EDin mg/Kg was determined for certain comri e p t oci cus 1 pounds of theinvention after intraperitoneal infection pyogenes w 100 andsubcutaneous (s.c.) or oral (p.c.) administratlon of the preparation.

Table 3 Compound of Compound of Compound of Compound of Example 3Example 8 Example 13 Example 14 Bacterium s.c. p.c. s.c. p.c. s.c. p.c.s.c. p.c.

Escherichia 50 I00 50 l ()0 25 50 l00 coli C 165 Staphylococ- 25 50 CUSaureus TABLE 2 In general, it has proved advantageous, in acute gen-Minimum inhibitory concentration (MIC) in 'y/ml of medium, measured bythe series dilution test (complete medium), incubation temperature: 37C, determination of the MIC after 18, 24 and 48 hours.

Compound of Bacterium Example 13 Streptococcus faecalis ATCC 9700 508564 I00 871 1 50 Streptococcus faecalis ATCC B. H, 100 Blaschke 6-25 I,H H '3 25 species 100 liquef. 50 durans 25 Escherichia coli C 165 50-1002 25-50 55 B 5 3-6 A 261 25-50 813/58 6-12 Proteus mirabilis G l 2 293512 vulgaris vulgaris 3400 50 I017 17 Pseudomonas aeruginosa W 400 H H M25 I, l. B 25 Klebsiella ATCC l003l l-2 K 10 50 63 50 Salmonellaparatyphii BB II [2 Corynebacterium diphteriae gravis 5-l0Staphylococcus aureus 133 l BRL l2 Neisseria catharalis N [/41 6Mycoplasma gallisepticum 6 Mycoplasma gallisepticum*) 6 granularum*) 3Mycobacterium tuberculosis H 37 RV )mcasured in u PPLO medium For thecompound of Example 3, the following minimal inhibitory concentrations(MIC) ('y/ml of nutrient medium) were measured by the series dilutiontest (PPLO medium), incubation temperature 37 C, determination after 18,24 and 48 hours.

eral infections, to administer amounts of about 5 mg to about 200 mg perkilogram, preferably about 25 to about 50 mg per kilogram of body weightper day, to achieve effective results. Nevertheless it can at times benecessary to deviate from the amounts mentioned, in particular dependingon the body weight of the test animal or patient or on the nature of themethod of administration, but also because of the type of animal and itsindividual behaviour towards the medicament, or because of the nature ofthe formulation of the latter, and the point in time or interval atwhich administration takes place. Thus it can, in some cases, suffice touse less than the abovementioned minimum amount, whilst in other casesthe upper limit mentioned must be exceeded. In the case of theadministration of larger amounts it can be advisable to divide theseinto several individual doses over the course of the day. The same rangeof dosages is envisaged for administration in human medicine. The othercomments made above also apply in a general sense.

Accordingly, the present invention provides a pharmaceutical compositioncontaining as an active ingredient as least one of the new compounds ofthe general formula (1) given above in admixture with a pharmaceuticallyacceptable solid or liquid diluent or carrier as hereinafter defined.

In the present specification the expression pharmaceutically acceptablediluent or carrier means a nontoxic substance that when mixed with theactive ingredient or ingredients renders it suitable for administration.The expression preferably excludes water and low-molecular weightorganic solvents commonly used in chemical synthesis, except in thepresence of other pharmaceutically necessary ingredients such as saltsin correct quantities to render the composition isotonic, buffers,surfactants, colouring and flavouring agents, and preservatives.Examples of suitable liquid diluents and carriers are vegetable oils,glycerol, propylene glycol, polyols, buffered aqueous solutions,isotonic saline aqueous solutions, syrups and lotion bases. Examples ofsuitable solid diluents and carriers are starches, cellulose and itsderivatives, sugars, stearates and stearic acid, talc, and ointmentbases. Examples of pharmaceutical compositions according to theinvention are ointments, pastes, creams, sprays, lotions, aqueous andnon-aqueous suspensions, emulsions, and solutions (includingparenterally injectable solutions), elixirs and syrups, and granulatesand powders either free-flowing or compressedinto tablets.

Pharmaceutical compositions of the invention adapted for oraladministration are a preferred embodiment of the invention. The diluentsand carriers used are preferably therefore those that adapt the activeingredient or ingredients for oral administration. Examples of suchdiluents and carriers are solid vehicles, excipients and lubricants suchas glucose, lactose and sucrose, corn and potato starch, sodiumcarboxymethylcellulose, ethyl cellulose and cellulose acetate, powderedgum tragacanth, gelatin, alginic acid, agar, talc, stearic acid andsodium, calcium and magnesium stearates, sodium lauryl sulphate,polyvinyl-pyrrolidone, sodium citrate, calcium carbonate, and dicalciumphosphate.

The pharmaceutical compositions of the invention may also contain othernon-toxic adjuvants and modifiers such as dyes, surfactants, perfumes,flavouring agents, such as sweeteners, preservatives and biocides.

Pharmaceutical compositions of the invention adapted for parenteralinjection are another preferred embodiment of the invention. Thediluents and carriers used are therefore preferably those that adapt theactive ingredient for parenteral administration. Examples of diluentsand carriers that adapt the active ingredient for parenteraladministration are solvents and suspending diluents such as water,vegetable fatty oils, such as sesame oil, groundnut oil, corn oil, andcottonseed oil, aqueous propylene glycol, N,N'-di-methylformamide, anddimethyl sulphoxide. In general, any non-aqueous diluent can be usedthat does not reduce the activity of the active ingredient and isnon-toxic in the dose employed.

For the administration of the water-soluble compounds of the inventionby parenteral injection sterile aqueous solutions can be employed, andare within the scope of the pharmaceutical compositions of theinvention. Such aqueous solutions should preferably when necessary bebuffered in the usual manner, and the liquid diluent should preferablybefore administration be rendered isotonic by adding the requisiteamount of salt or glucose. Such sterile buffered isotonic solutions areespecially suitable for intravenous, intramuscular and intraperitonealinjections. These pharmaceutical compositions of the invention canfurther contain local anaesthetics or substances that promote thediffusion of the active ingredient, for example hyaluronidase,

The pharmaceutical compositions of the invention preferably contain 0.5to 90 wt.% of at least one new compound of the invention.

The present invention also provides medicaments in dosage unit form ashereinafter defined comprising as an active ingredient at least onecompound of general formula 1) given above either along or in admixturewith a pharmaceutically acceptable solid or liquid diluent or carrier.In this case the diluent or carrier is pref erably as defined above butcan also be water or another common solvent.

The expression medicament in dosage unit form as used in the presentspecification means a medicament in the form of discrete portions eachcontaining a unit dose or a multiple or sub-multiple ofa unit dose ofthe active ingredient(s); for example, one, two, three or four unitdoses or a half, a third or a quarter of a unit dose. A unit dose is theamount of the active ingredient(s) to be administered on one occasionand will usually be a daily dose, or for example a half, a third, or aquarter of a daily dose depending on whether the medicament is to beadministered once or, for example, twice, three times, or four times aday.

The discrete portions constituting the medicament in dosage unit formcan include a protective envelope. The active ingredient can beundiluted and contained in such an envelope, or can be mixed with apharmaceutically acceptable solid or liquid diluent or carrier asdefined above. Such portions can for example be in monolithic coherentform, such as tablets, lozenges, pastilles, pills, suppositories, ordragees; in wrapped or concealed form, the active ingredients beingwithin a protective envelope, such as wrapped powders, cachets, sachets,capsules, or ampoules; or in the form of a sterile solution suitable forparenteral injection, such as ampoules of buffered, isotonic, sterile,pyrogen-free aqueous solution; or in any other form known in the art.

As stated above, peroral administration is a preferred mode ofadministration. Preferred medicaments in dosage unit form according tothe invention are therefore those adapted for oral administration, suchas tablets, pills, dragees, capsules, and cachets, as well as wrappedpowders containing the active ingredient in powdered form with apowdered diluent or carrier for suspension in water before being taken.

As also stated above a further preferred mode of administration isparenteral administration. Preferred medicaments in dosage unit formaccording to the invention are therefore those adapted for parenteralinjection, such as ampoules containing a measured quantive ingredient,preferably 1250 4000 mg. This will usually be administered once daily.

The invention further provides a method of combatting bacterialinfection in an animal which comprises administering to the animal(preferably parenterally or perorally) an effective amount of one of thenew compounds, either alone, as a pharmaceutical composition accordingto the invention, or as a medicament in dosage unit form according tothe invention.

Indications envisaged in human medicine are especially generalinfections, and infections of the efferent urinary tract, caused byGram-positive and Gramnegative bacteria and by mycoplasma, and inveterinary medicine are general infections caused by Gramnegative andGram-positive bacteria and my mycoplasma. Infections of the respiratorypassages in poul try, especially in chicks, and mastitis of cows, may bementioned particularly The new compounds can, as has already beenmentioned, also be employed as a feedstuff additive, predominantly inraising young animals, especially chicks and fatstock.

The preparations can be administered in the feedstuff, special feedstuffpreparations and feedstuff concentrates, but also via the drinkingwater.

The invention therefore also provides animal feedstuffs and feedstuffconcentrates containing at least one of the new compounds of generalformula (1).

The administration of the new compounds together with the feedstuff orfeedstuff preparations and/or with the drinking water makes it possibleto prevent or treat infections by both Gram-negative and Gram-positivebacteria and mycoplasma, and can furthermore contribute to betterutilization of the feedstuff. As examples of frequently occurringveterinary illnesses which cause considerable economic damage and whichcan be prevented or treated by administering the new compounds in thefeedstuff or in the drinking water, there may be mentioned, in additionto general infections, infection of the air sac in chicks, and mastitisin cows.

What is claimed is:

1. An antibacterial composition which comprises an antibacteriallyeffective amount of a compound of the formula N OOY i CH=NR O or apharmaceutically acceptable non-toxic salt thereof wherein Y ishydrogen, an alkali metal cation or the cation R NH and each of R and Ris alkyl of 1 to 6 carbon atoms, hydroxy alkyl of l to 6 carbon atoms,cyclopropyl, cyclopentyl, cyclohexyl, or norbornyl, in combination witha pharmaceutically acceptable non-toxic inert diluent or carrier.

2. An antibacterial composition according to claim 1 wherein each of Rand R is alkyl of l to 4 carbon atoms, hydroxyalkyl of l to 4 carbonatoms, or cyclohexyl.

3. An antibacterial composition according to claim 1 wherein each of Rand R is alkyl of l or 2 carbon atoms or hydroxyalkyl of l or 2 carbonatoms.

4. An antibacterial composition according to claim 1 wherein each of Rand R is alkyl of l to 4 carbon atoms.

5. An antibacterial composition according to claim 1 wherein each of Rand R is hydroxyalkyl of l to 4 carbon atoms.

6. An antibacterial composition according to claim 1 wherein each of Rand R is cyclohexyl.

7. An antibacterial composition according to claim 1 wherein Y ishydrogen.

8. An antibacterial composition according to claim 1 wherein Y is thesodium or potassium cation.

9. An antibacterial composition according to claim 1 in oraladministration form.

10. An antibacterial composition according to claim 1 in subcutaneousadministration form.

11. An antibacterial composition according to claim 1 wherein thecompound is H not? a r-c' CH ,5 H I 3 1 H==N u ca 10 12. Anantibacterial compbsition according to claim 1 wherein the compound is14. An antibacterial composition according to claim 1 wherein thecompound is Q (a 0O H N 0 1-1 g CH=NC H 15. An antibacterial compositionaccording to claim 1 wherein the compound is 16. An antibacterialcomposition according to claim 1 wherein the compound is;

. H e a 33 7 *f s 17. An antibacterial composition according to claim 1wherein the compound is 18. An antibacterial composition accordingtoclaim 1 wherein the compound is 19. An antibacterial compositionaccording to claim 1 wherein the compound is CH==NCH -Cl'l OH 20. Amethod of treating bacterial infections in hu mans and animals whichcomprises administering to said human or animal an antibacteriallyeffective amount of a compound of the formula if .0. d rt...

or a pharmaceutically acceptable non-toxic salt thereof wherein Y ishydrogen, an alkali metal cation or the cation each of R and R is alkylof 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms,cyclopropyl, cyclopentyl, cyclohexyl, or norbornyl, in combination witha pharmaceutically acceptable non-toxic inert diluent or carrier.

21. A method according to claim 20 wherein each of R and R is alkyl of 1to 4 carbon atoms, hydroxyalkyl of l to 4 carbon atoms, or cyclohexyl.

22. A method according to claim 20 wherein each of R and R is alkyl of lor 2 carbon atoms or hydroxyalkyl of 1 or 2 carbon atoms.

23. A method according to claim 20 wherein each of R and R is alkyl of lto 4 carbon atoms.

24. A method according to claim 20 wherein each of R and R ishydroxyalkyl of l to 4 carbon atoms.

25. A method according to claim 20 wherein each of R and R iscyclohexyl.

26. A method according to claim 20 wherein Y is hydrogen.

27. A method according to claim 20 wherein Y is the sodium or potassiumcation.

28 A method according to claim 20 wherein the administration is oral.

29. A method according to claim 20 wherein the administration is bysubcutaneous injection.

30. The method according to claim 20 wherein the compound is 31. Themethod according to claim 20 wherein the compound is 32. The methodaccording to claim 20 wherein the compound is COO H NCH CPR-CH 33. Themethod according to claim 20 wherein the compound is CH=NC- H ll Z 34.The method according to claim wherein the 10 compound is 36. The methodaccording to claim 20 where n the compound is 37. The method accordingto claim 20 wherein the compound is i W 1 il lcgg 38. The methodaccording to claim 20 wherein the compound is

1. AN ANTIBACTERIAL COMPOSITION WHICH COMPRISES AN ANTIBACTERICALLYEFFECTIVE AMOUNT OF A COMPOUND OF THE FORMULA
 2. An antibacterialcomposition according to claim 1 wherein each of R and R5 is alkyl of 1to 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms, or cyclohexyl.3. An antibacterial composition according to claim 1 wherein each of Rand R5 is alkyl of 1 or 2 carbon atoms or hydroxyalkyl of 1 or 2 carbonatoms.
 4. An antibacterial composition according to claim 1 wherein eachof R and R5 is alkyl of 1 to 4 carbon atoms.
 5. An antibacterialcomposition according to claim 1 wherein each of R and R5 ishydroxyalkyl of 1 to 4 carbon atoms.
 6. An antibacterial compositionaccording to claim 1 wherein each of R and R5 is cyclohexyl.
 7. Anantibacterial composition according to claim 1 wherein Y is hydrogen. 8.An antibacterial composition according to claim 1 wherein Y is thesodium or potassium cation.
 9. An antibacterial composition according toclaim 1 in oral administration form.
 10. An antibacterial compositionaccording to claim 1 in subcutaneous administration form.
 11. Anantibacterial composition according to claim 1 wherein the compound is12. An antibacterial composition according to claim 1 wherein thecompound is
 13. An antibacterial composition according to claim 1wherein the compound is
 14. An antibacterial composition according toclaim 1 wherein the compound is
 15. An antibacterial compositionaccording to claim 1 wherein the compound is
 16. An antibacterialcomposition according to claim 1 wherein the compound is
 17. Anantibacterial composition according to claim 1 wherein the compound is18. An antibacterial composition according to claim 1 wherein thecompound is
 19. An antibaCterial composition according to claim 1wherein the compound is
 20. A method of treating bacterial infections inhumans and animals which comprises administering to said human or animalan antibacterially effective amount of a compound of the formula
 21. Amethod according to claim 20 wherein each of R and R5 is alkyl of 1 to 4carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms, or cyclohexyl.
 22. Amethod according to claim 20 wherein each of R and R5 is alkyl of 1 or 2carbon atoms or hydroxyalkyl of 1 or 2 carbon atoms.
 23. A methodaccording to claim 20 wherein each of R and R5 is alkyl of 1 to 4 carbonatoms.
 24. A method according to claim 20 wherein each of R and R5 ishydroxyalkyl of 1 to 4 carbon atoms.
 25. A method according to claim 20wherein each of R and R5 is cyclohexyl.
 26. A method according to claim20 wherein Y is hydrogen.
 27. A method according to claim 20 wherein Yis the sodium or potassium cation.
 28. A method according to claim 20wherein the administration is oral.
 29. A method according to claim 20wherein the administration is by subcutaneous injection.
 30. The methodaccording to claim 20 wherein the compound is
 31. The method accordingto claim 20 wherein the compound is
 32. The method according to claim 20wherein the compound is
 33. The method according to claim 20 wherein thecompound is
 34. The method according to claim 20 wherein the compound is35. The method according to claim 20 wherein the compound is
 36. Themethod according to claim 20 wherein the compound is
 37. The methodaccording to claim 20 wherein the compound is
 38. The method accordingto claim 20 wherein the compound is